CN101747328A - Synthesis method of single-ring imipenem p-nitro benzyl ester - Google Patents
Synthesis method of single-ring imipenem p-nitro benzyl ester Download PDFInfo
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- CN101747328A CN101747328A CN200910231289A CN200910231289A CN101747328A CN 101747328 A CN101747328 A CN 101747328A CN 200910231289 A CN200910231289 A CN 200910231289A CN 200910231289 A CN200910231289 A CN 200910231289A CN 101747328 A CN101747328 A CN 101747328A
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Abstract
The invention belongs to the technical field of medicines and in particular discloses a synthesis method of single-ring imipenem p-nitro benzyl ester. In the method, 6-APA is used as a raw material, and the single-ring imipenem p-nitro benzyl ester is prepared through reactions of nitration, bromination, oxidation, esterification, ring-opening, and the like. The method is characterized in that noval reagents and catalysts are adopted during synthesis, a single aromatic organic solvent is used as a reaction solvent, and an obtained product is easy to recover and convenient to apply. In the synthesis process, a one-pot synthesis method is adopted, thereby simplifying the process flow and shortening the production period.
Description
(1) technical field
The invention belongs to medical technical field, particularly a kind of monocycle training south is to the synthetic method of nitrobenzyl ester.
(2) background technology
Monocycle training south is a kind of novel ss-lactam enzyme inhibitors intermediate to the nitrobenzyl ester.Beta-lactamase inhibitor belongs to the beta-lactam medicine series, pathogenic bacteria produces β-Nei Xiananmei through the plasmid transmission, cause some medicines (penicillins, cephalosporin etc.) that the lactam nucleus hydrolysis takes place and inactivation is that pathogenic bacteria is to the drug-fast main mode of some common β-Nei Xiananleikangshengsus.In order to overcome this resistance, except development has the new antibiotic of anti-enzyme performance, also need beta-lactamase inhibitor.
Monocycle training south to its structural formula of nitrobenzyl ester is:
Comprehensive literature report monocycle training south mainly is summed up as following synthetic route to the synthetic route of nitrobenzyl ester:
With 6-amino-penicillanic acid (6-APA) is starting raw material, carry out bromo-reaction with liquid bromine, sulfuric acid earlier, generate the penicillanic acid sulfoxide with the Peracetic Acid oxidizing and crystallizing again, then with nitro benzyl bromide is reacted the carboxylate crystallization, the last reaction with mercaptobenzothiazole obtains product.
There are a lot of defectives in this operational path, and products obtained therefrom is of poor quality, and complicated operation is seriously polluted.
(3) summary of the invention
The present invention provides the synthetic method of the monocycle training south of a kind of good product quality, easy handling to the nitrobenzyl ester in order to remedy the deficiencies in the prior art.
The present invention is achieved through the following technical solutions:
A kind of monocycle training south comprises the steps: the synthetic method of nitrobenzyl ester
(1) with the 6-amino-penicillanic acid be raw material, the interpolation dilute sulphuric acid is a catalyzer, carries out bromo-reaction in the single fragrant same clan organic solvent under-25～0 ℃, obtains 6 α-bromo-penicillanic acid solution;
Investigate the influence of bromo condition to 6 α-bromo-penicillanic acid by experiment, experimental data is as follows:
| Batch | Temperature of reaction/℃ | Brominated reagent | Yield |
| ??1 | ??0～-5 | Bromine | ??81.0％ |
| Batch | Temperature of reaction/℃ | Brominated reagent | Yield |
| ??2 | ??0～-5 | Potassium Bromide | ??82.5％ |
| ??3 | ??-10～-15 | The N-bromo-succinimide | ??84.2％ |
| ??4 | ??-10～-15 | Potassium Bromide | ??88.2％ |
| ??5 | ??-20～-25 | Bromine | ??83.2％ |
| ??6 | ??-20～-25 | Potassium Bromide | ??84.8％ |
Bromizating agent in this step is hydrogen bromide, bromine, N-bromo-succinimide and bromine salt, the Potassium Bromide in the preferred bromine salt; Preferred-15～-10 ℃ of the temperature of bromo-reaction.
(2) under-10～15 ℃, in 6 α-bromine penicillanic acid solution, add catalyzer and oxygenant, oxidation obtains 6 α-bromine penicillanic acid sulfoxide solution;
Investigate the influence of oxidizing condition to the acid of bromo mould sulfoxide by experiment, experimental data is as follows:
| Batch | Temperature of reaction/℃ | Reaction times/h | Yield |
| ??1 | ??-5～-10 | ??4.5 | ??86.4％ |
| ??2 | ??0～-5 | ??3 | ??85.8％ |
| ??3 | ??0～5 | ??2.5 | ??90.0％ |
| ??4 | ??5～10 | ??2 | ??86.2％ |
| ??5 | ??10～15 | ??1 | ??85.2％ |
| ??6 | ??15～20 | ??0.5 | ??83.2％ |
As seen from the above table, preferred 0～5 ℃ of the temperature of oxidizing reaction, preferred 2.5 hours of reaction times.
Investigate the influence to 6 α-bromine penicillanic acid sulfoxide of oxygenant and catalyzer by experiment, experimental data is as follows:
| Batch | Oxygenant | Catalyzer | Yield |
| ??1 | Hydrogen peroxide | The molybdenum ammonium vanadate | ??98.9％ |
| ??2 | Peracetic Acid | ??--- | ??94.2％ |
| ??3 | Potassium bichromate | Tetramethyl Ethylene Diamine | ??94.6％ |
| Batch | Oxygenant | Catalyzer | Yield |
| ??4 | Potassium Persulphate | N, the N-dimethyl benzylamine | ??94.3％ |
| ??5 | Potassium permanganate | Sulfuric acid | ??93.7％ |
| ??6 | Manganse Dioxide | Ammonium meta-vanadate | ??93.2％ |
In this step, described oxygenant is one or more in hydrogen peroxide, Peracetic Acid, potassium bichromate, Potassium Persulphate, potassium permanganate, the Manganse Dioxide, preferred hydrogen peroxide; Ammonium vanadate class material is molybdenum ammonium vanadate, ammonium meta-vanadate, Tetramethyl Ethylene Diamine, N, one or more in N-dimethyl benzylamine and the sulfuric acid, preferred molybdenum ammonium vanadate.
(3) in 6 α-bromine penicillanic acid sulfoxide solution, add a kind of in soluble carbon hydrochlorate and TBAH, Tetrabutyl amonium bromide, the four heptyl brometo de amonios, 10～12 ℃ drip down nitro benzyl bromide generation esterification, dripping the frozen water layering below 10 ℃ then, cast out water, obtain 6 α-bromine penicillanic acid sulfoxide esters solution;
(4) 6 α-bromine penicillanic acid sulfoxide esters solution adds mercaptobenzothiazole down at 70～120 ℃, after reduced-pressure backflow is removed moisture and aromatic series organism in aromatic organic solvent, be cooled to be evaporated to below 60 ℃ dried, crystal is separated out in the dissolving cooling, growing the grain filters after scouring, and oven dry obtains product monocycle training south to the nitrobenzyl ester.
Investigate open loop condition by experiment to the influence of monocycle training south to the nitrobenzyl ester, experimental data is as follows:
| Batch | Temperature of reaction ℃ | Reaction times h | Product purity | Product yield |
| ??1 | ??70～75 | ??8 | ??95.5％ | ??82.9％ |
| ??2 | ??75～80 | ??6 | ??96.3％ | ??83.0％ |
| ??3 | ??80～90 | ??5 | ??98.5％ | ??83.1％ |
| ??4 | ??90～100 | ??4 | ??98.8％ | ??83.2％ |
| ??5 | ??100～105 | ??4 | ??99.7％ | ??90.2％ |
| ??6 | ??120～130 | ??3 | ??95.3％ | ??83.1％ |
As can be seen from the above table, when temperature was higher than 120 ℃, impurity was higher, and qualification rate is low, and temperature is below 100 ℃ the time, and the reaction times is longer, and energy consumption is bigger, influences the Workshop Production progress, and therefore only band water temp is 100～105 ℃.
In this step, described aromatic organic solvent is toluene, benzene, dimethylbenzene and rudimentary aromatic series solvent, preferred toluene.
Building-up reactions route of the present invention is as follows:
The present invention has the following advantages:
(1) preparation process is simple, and convenient post-treatment is easy to suitability for industrialized production;
(2) preparation feedback adopts single solvent, is easy to the recovery of solvent and applies mechanically, and has simplified operation;
(3) reactions steps is shorter, the product yield height, and the three wastes are handled more or less freely.
The present invention has adopted step process operation in building-up process, simplified process engineering, has shortened the production cycle, reduces power consumption, reduces production costs, and improves product yield, is beneficial to industrial practicing.
(4) embodiment
Embodiment 1
Synthetic (bromo) of (1) 6 α-bromo-penicillanic acid
In 1000 liters of reactors, add 470 kg of water, be cooled to 0～5 ℃, add 35 kilogram of 98% sulfuric acid.Treat after adding that temperature reduces to-10 ℃ of next coming in order and add 120.2 kilograms of Potassium Bromides, 43.2 kilograms of 6-APA and 120 kg toluene.Add the question response temperature and descend below-10 ℃, begin to drip 100 kilograms of 20% sodium nitrite in aqueous solution, control reaction temperature is-15～-10 ℃ of 1h.Dropwised back temperature control stirring reaction 4 hours, Liquid Detection 6-APA is less than 0.5%.Add 150 kilograms of toluene,, filter at stirring reaction 30min below 10 ℃, layering, water merges organic phase 50 kilograms of washings of saturated aqueous common salt with 50 kilograms of extractions of toluene, water 20 kilograms of extractions of toluene after the organic phase layering, it is standby to merge organic phase.
Synthetic (oxidation) of (2) 6 α-bromo-mould sulfoxide alkanoic acid
500 liters of reactors, step 6 α-bromo-penicillanic acid and toluene mixture in the adding is under 8 ℃ temperature, add 0.5 kilogram of catalyzer molybdenum vanadium phosphate ammonium, slowly be added dropwise to 50% hydrogen peroxide 120 kg, add 0～5 ℃ of reaction in back 3h, Liquid Detection 6 α-bromo-penicillanic acid is less than 0.3%.Lower the temperature 0～5 ℃ and slowly drip 10 kilogram of 30% dilute sulphuric acid to the reaction solution water white transparency, temperature control reaction 30 minutes, reaction solution is poured in 227 kilograms of saturated sodium bisulfites, stir layering, organic phase is respectively washed once for 90 kilograms with saturated sodium bicarbonate and saturated aqueous common salt, 40 kilograms of anhydrous sodium sulfate dryings filter standby.
Synthetic (esterification) of (3) 6 α-bromo-mould sulfoxide alkane acid benzyl ester
Up go on foot in 6 α-bromo-mould sulfoxide alkanoic acid toluene solution and to add 0.2 kilogram of TBAH, be cooled to 0～5 ℃, drip nitro benzyl bromide, 9～12 ℃ of reaction 4h, Liquid Detection, remaining less than 0.5%.Temperature control drips 200 kilograms of frozen water below 10 ℃, about 1h dropwises, and filters layering, adds 200 kilograms of layerings of aqueous hydrochloric acid of 3%, and organic phase adds 30 kilograms of drying for standby of anhydrous magnesium sulfate.
(4) monocycle training south is to synthetic (open loop) of nitrobenzyl ester
1000 liters of reactors that have division box, ground beetle benzene penicillanic acid is to nitrobenzyl ester sulfoxide in the adding, 100 ℃ of backflow 30min of decompression intensification, discard water and the toluene told, add 43.3 kilograms of mercaptobenzothiazoles down in 80 ℃, reduce pressure 110 ℃ and refluxed 2 hours, the Liquid Detection penicillanic acid to nitrobenzyl ester sulfoxide remnants less than 0.3%, be cooled to be evaporated to below 45 ℃ dried, add 240 kilograms of ether and 60 kilograms of dissolvings of chloroform, crystal is separated out in cooling, and heating and cooling growing the grain 2h filters, the washing of 5 kilograms of ice ether, dry 11.3 kilograms of products, purity is greater than 99%, fusing point 78-81 ℃.
Embodiment 2
Synthetic (bromo) of (1) 6 α-bromo-penicillanic acid
In 1000 liters of reactors, add 400 kg of water, be cooled to 0～5 ℃, add 35 kilogram of 98% sulfuric acid.Treat after adding that temperature reduces to-10 ℃ of next coming in order and add 120.2 kilograms of Potassium Bromides, 43.2 kilograms of 6-APA and 120 kg toluene.Add the question response temperature and descend below-10 ℃, begin to drip 21.2 kilograms, 100 kg of water solution of Sodium Nitrite, control reaction temperature is-13～-15 ℃ of 1.5h.Dropwised back temperature control stirring reaction 2 hours, Liquid Detection 6-APA is less than 0.5%.Add 150 kilograms of toluene, stirring 30min below 10 ℃, filter, layering, water 30 kilograms of extractions of toluene, the merging organic phase is washed with saturated aqueous common salt 50 milli kilograms, water 20 kilograms of extractions of toluene after the organic phase layering, it is standby to merge organic phase.
Synthetic (oxidation) of (2) 6 α-bromo-mould sulfoxide alkanoic acid
500 liters of reactors add 6 α-bromo-penicillanic acid and toluene mixture, after the dissolving, under 5 ℃ temperature, add 0.5 kilogram of catalyzer molybdenum vanadium phosphate ammonium, slowly be added dropwise to 50% hydrogen peroxide 120 kg, add 0～5 ℃ of reaction in back 3h, Liquid Detection 6 α-bromo-penicillanic acid is less than 0.5%.Lowering the temperature 0 ℃ slowly drips 15 kilogram of 30% dilute sulphuric acid to the reaction solution water white transparency, temperature control reaction 30 minutes.Reaction solution is poured in 227 kilograms of saturated sodium bisulfites, stirred layering, organic phase is respectively washed once with saturated sodium bicarbonate and saturated aqueous common salt, and 40 kilograms of anhydrous sodium sulfate dryings filter standby.
Synthetic (esterification) of (3) 6 α-bromo-mould sulfoxide alkane acid benzyl ester
Up go on foot in 6 α-bromo-mould sulfoxide alkanoic acid toluene solution and to add 0.3 kilogram of Tetrabutyl amonium bromide, be cooled to 0～5 ℃, drip nitro benzyl bromide, 9～10 ℃ of reaction 4h, Liquid Detection, remaining less than 0.5%.Temperature control drips 200 kilograms of frozen water below 10 ℃, about 1h dropwises, and filters layering, adds 200 kilograms of layerings of aqueous hydrochloric acid of 3%, and organic phase adds 30 kilograms of drying for standby of anhydrous magnesium sulfate.
(4) monocycle training south is to synthetic (open loop) of nitrobenzyl ester
1000 liters of reactors that have division box, ground beetle benzene penicillanic acid is to nitrobenzyl ester sulfoxide in the adding, 95 ℃ of backflow 30min of decompression intensification, discard water and the toluene told, adding 43.3 kilograms of decompressions of mercaptobenzothiazole down in 80 ℃ refluxed 2 hours for 100～105 ℃, the Liquid Detection penicillanic acid to nitrobenzyl ester sulfoxide remnants less than 0.3%, be cooled to and be evaporated to driedly below 45 ℃, add 200 kilograms of ether and 40 kilograms of dissolvings of chloroform, crystal is separated out in cooling, heating and cooling growing the grain 2h, filter, the washing of 5 kilograms of ice ether, dry 11 kilograms of products, purity is greater than 99%, fusing point 78-81 ℃.
Claims (9)
1. the southern synthetic method to the nitrobenzyl ester of monocycle training is characterized in that: comprise the steps:
(1) is raw material with the 6-amino-penicillanic acid, carries out bromo-reaction in the single fragrant same clan organic solvent under-25～0 ℃, obtain 6 α-bromine penicillanic acid solution;
(2) under-10～15 ℃, in 6 α-bromine penicillanic acid solution, add catalyzer and oxygenant, oxidation obtains 6 α-bromine penicillanic acid sulfoxide solution;
(3) in 6 α-bromine penicillanic acid sulfoxide solution, add quarternary ammonium salt compound and soluble carbon hydrochlorate, 10～12 ℃ drip down nitro benzyl bromide generation esterification, dripping the frozen water layering below 10 ℃, cast out water then, obtain 6 α-bromine penicillanic acid sulfoxide esters solution;
(4) 6 α-bromine penicillanic acid sulfoxide esters solution adds mercaptobenzothiazole down at 70～120 ℃, after reduced-pressure backflow is removed moisture and aromatic series organism in aromatic organic solvent, be cooled to be evaporated to below 60 ℃ dried, adding ethers and halo alkanes are compounded with machine lyase dissolving cooling and separate out crystal, growing the grain filters after scouring, and oven dry obtains product monocycle training south to the nitrobenzyl ester.
2. monocycle training according to claim 1 south is to the synthetic method of nitrobenzyl ester, and it is characterized in that: the bromizating agent in the step (1) is hydrogen bromide, bromine, N-bromo-succinimide and bromine salt, the Potassium Bromide in the preferred bromine salt; The preferred toluene of single fragrant same clan organic solvent.
3. monocycle training according to claim 1 and 2 south is to the synthetic method of nitrobenzyl ester, and it is characterized in that: in the step (1), the temperature of bromo-reaction is-15～-10 ℃.
4. monocycle training according to claim 1 and 2 south is to the synthetic method of nitrobenzyl ester, it is characterized in that: in the step (2), described catalyzer is molybdenum ammonium vanadate, ammonium meta-vanadate, Tetramethyl Ethylene Diamine, N, one or more in N-dimethyl benzylamine, the sulfuric acid, preferred molybdenum ammonium vanadate.
5. monocycle training according to claim 1 and 2 south is to the synthetic method of nitrobenzyl ester, it is characterized in that: in the step (2), described oxygenant is one or more in hydrogen peroxide, Peracetic Acid, potassium bichromate, Potassium Persulphate, potassium permanganate, the Manganse Dioxide, preferred hydrogen peroxide.
6. monocycle training according to claim 1 and 2 south is to the synthetic method of nitrobenzyl ester, and it is characterized in that: in the step (2), the temperature of described oxidizing reaction is 0～5 ℃.
7. monocycle training according to claim 1 and 2 south is to the synthetic method of nitrobenzyl ester, and it is characterized in that: in the step (3), described quarternary ammonium salt compound is TBAH, Tetrabutyl amonium bromide, four heptyl brometo de amonios, preferred TBAH.
8. monocycle training according to claim 1 and 2 south is to the synthetic method of nitrobenzyl ester, and it is characterized in that: in the step (4), described aromatic organic solvent is toluene, benzene, dimethylbenzene and rudimentary aromatic series solvent, preferred toluene.
9. monocycle training according to claim 1 and 2 south is to the synthetic method of nitrobenzyl ester, and it is characterized in that: in the step (4), temperature of reaction is 100～105 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004231A (en) * | 2019-12-18 | 2020-04-14 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of tazobactam intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004231A (en) * | 2019-12-18 | 2020-04-14 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of tazobactam intermediate |
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